BRPI1008779A2 - Compostos como antagonistas de bradiquinina-b1 - Google Patents
Compostos como antagonistas de bradiquinina-b1 Download PDFInfo
- Publication number
- BRPI1008779A2 BRPI1008779A2 BRPI1008779-6A BRPI1008779A BRPI1008779A2 BR PI1008779 A2 BRPI1008779 A2 BR PI1008779A2 BR PI1008779 A BRPI1008779 A BR PI1008779A BR PI1008779 A2 BRPI1008779 A2 BR PI1008779A2
- Authority
- BR
- Brazil
- Prior art keywords
- alkyl
- group
- fluorine atoms
- substituted
- radicals
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 213
- 239000005557 antagonist Substances 0.000 title abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 444
- 150000003839 salts Chemical class 0.000 claims abstract description 156
- 239000000203 mixture Substances 0.000 claims abstract description 98
- 150000007524 organic acids Chemical class 0.000 claims abstract description 48
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 44
- 239000003814 drug Substances 0.000 claims abstract description 16
- 230000008569 process Effects 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- -1 alkylene radical Chemical class 0.000 claims description 598
- 150000003254 radicals Chemical class 0.000 claims description 176
- 125000001153 fluoro group Chemical group F* 0.000 claims description 163
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 135
- 229910052731 fluorine Inorganic materials 0.000 claims description 118
- 229910052739 hydrogen Inorganic materials 0.000 claims description 88
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 87
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 81
- 229910052801 chlorine Inorganic materials 0.000 claims description 69
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 69
- 229910052736 halogen Inorganic materials 0.000 claims description 65
- 150000002367 halogens Chemical class 0.000 claims description 65
- 229910052757 nitrogen Inorganic materials 0.000 claims description 50
- 229910052794 bromium Inorganic materials 0.000 claims description 49
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 41
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 39
- 229910052799 carbon Inorganic materials 0.000 claims description 38
- 229910052760 oxygen Inorganic materials 0.000 claims description 30
- 125000004429 atom Chemical group 0.000 claims description 27
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 27
- 208000002193 Pain Diseases 0.000 claims description 25
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 25
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 23
- 239000011737 fluorine Substances 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 230000036407 pain Effects 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 20
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 18
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 11
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- 229910052700 potassium Inorganic materials 0.000 claims description 9
- 125000004434 sulfur atom Chemical group 0.000 claims description 9
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 9
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 8
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 8
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 8
- 125000002971 oxazolyl group Chemical group 0.000 claims description 8
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 8
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 8
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 8
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 8
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 8
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 8
- 125000000335 thiazolyl group Chemical group 0.000 claims description 8
- 125000004306 triazinyl group Chemical group 0.000 claims description 8
- 125000001425 triazolyl group Chemical group 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- 208000006673 asthma Diseases 0.000 claims description 7
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 7
- 150000007530 organic bases Chemical class 0.000 claims description 7
- 230000001154 acute effect Effects 0.000 claims description 6
- 229910052791 calcium Inorganic materials 0.000 claims description 6
- 208000004296 neuralgia Diseases 0.000 claims description 6
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 5
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 5
- 201000008482 osteoarthritis Diseases 0.000 claims description 5
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- 229910052759 nickel Inorganic materials 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 3
- 108010081348 HRT1 protein Hairy Proteins 0.000 claims description 3
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 3
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- 239000003085 diluting agent Substances 0.000 claims description 3
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- 238000011321 prophylaxis Methods 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 208000004998 Abdominal Pain Diseases 0.000 claims description 2
- 101100081489 Drosophila melanogaster Obp83a gene Proteins 0.000 claims description 2
- 206010016275 Fear Diseases 0.000 claims description 2
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- 102100021850 Nardilysin Human genes 0.000 claims description 2
- 108090000970 Nardilysin Proteins 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 101100113485 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) chs-3 gene Proteins 0.000 claims 3
- BSFODEXXVBBYOC-UHFFFAOYSA-N 8-[4-(dimethylamino)butan-2-ylamino]quinolin-6-ol Chemical compound C1=CN=C2C(NC(CCN(C)C)C)=CC(O)=CC2=C1 BSFODEXXVBBYOC-UHFFFAOYSA-N 0.000 claims 1
- 102100021580 Active regulator of SIRT1 Human genes 0.000 claims 1
- 101000988966 Escherichia coli Heat-stable enterotoxin A3/A4 Proteins 0.000 claims 1
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- 241000670573 Narcosius parisi helen Species 0.000 claims 1
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- URGUBECARCAPRI-UHFFFAOYSA-N tirandamycin A Natural products O1C(C2(OC2C2=O)C)(C)OC2C(C)C1C(C)C=C(C)C=CC(O)=C1C(=O)CNC1=O URGUBECARCAPRI-UHFFFAOYSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 33
- 229940079593 drug Drugs 0.000 abstract description 6
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- 238000004949 mass spectrometry Methods 0.000 description 109
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- 239000012071 phase Substances 0.000 description 93
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 90
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 87
- 239000000243 solution Substances 0.000 description 87
- 239000000543 intermediate Substances 0.000 description 83
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 74
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 73
- 238000001819 mass spectrum Methods 0.000 description 70
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 69
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 67
- 125000004093 cyano group Chemical group *C#N 0.000 description 66
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 59
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- LRJLOHRZWYRCRK-UHFFFAOYSA-N 1-(pyrimidine-5-carbonylamino)cyclopropane-1-carboxylic acid Chemical compound C=1N=CN=CC=1C(=O)NC1(C(=O)O)CC1 LRJLOHRZWYRCRK-UHFFFAOYSA-N 0.000 description 33
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- 238000006243 chemical reaction Methods 0.000 description 32
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- YUCFVHQCAFKDQG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH] YUCFVHQCAFKDQG-UHFFFAOYSA-N 0.000 description 26
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- QDXGKRWDQCEABB-UHFFFAOYSA-N pyrimidine-5-carboxamide Chemical compound NC(=O)C1=CN=CN=C1 QDXGKRWDQCEABB-UHFFFAOYSA-N 0.000 description 24
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
- 150000001408 amides Chemical class 0.000 description 18
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- IIVUJUOJERNGQX-UHFFFAOYSA-N pyrimidine-5-carboxylic acid Chemical compound OC(=O)C1=CN=CN=C1 IIVUJUOJERNGQX-UHFFFAOYSA-N 0.000 description 18
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 17
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 15
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
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- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 11
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- SQVRNKJHWKZAKO-PFQGKNLYSA-N N-acetyl-beta-neuraminic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-PFQGKNLYSA-N 0.000 description 10
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| EP09153778.7 | 2009-02-26 | ||
| EP09153778 | 2009-02-26 | ||
| PCT/EP2010/052232 WO2010097372A1 (de) | 2009-02-26 | 2010-02-23 | Verbindungen als bradykinin-b1-antagonisten |
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Families Citing this family (19)
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| DE102007034620A1 (de) * | 2007-07-25 | 2009-01-29 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue B1-Antagonisten |
| JP5238812B2 (ja) | 2007-08-29 | 2013-07-17 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 新規ブラジキニンb1アンタゴニスト |
| CA2694401C (en) | 2007-08-31 | 2012-12-04 | Eisai R&D Management Co., Ltd. | Polycyclic compound |
| KR20110118626A (ko) | 2009-02-26 | 2011-10-31 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 테트라하이드로트리아졸로피리딘 유도체의 염과 이의 결정 |
| MY153941A (en) * | 2009-02-26 | 2015-04-15 | Boehringer Ingelheim Int | Compounds as bradykinin b1 antagonists |
| AU2010218714A1 (en) | 2009-02-26 | 2011-09-08 | Eisai R&D Management Co., Ltd. | Nitrogen-containing fused heterocyclic compounds and their use as beta amyloid production inhibitors |
| SI2539323T1 (sl) * | 2010-02-23 | 2015-03-31 | Boehringer Ingelheim International Gmbh | Spojine kot antagonisti bradikinina B1 |
| EP2606043B1 (de) | 2010-08-20 | 2014-07-09 | Boehringer Ingelheim International GmbH | Pyridazinderivative als bradykinin b1 rezeptor antagonsiten |
| US8937073B2 (en) | 2010-08-20 | 2015-01-20 | Boehringer Ingelheim International Gmbh | Disubstituted tetrahydrofuranyl compounds and their use as B1-receptor antagonists |
| HUP1000598A2 (en) * | 2010-11-05 | 2012-09-28 | Richter Gedeon Nyrt | Indole derivatives |
| US8912221B2 (en) * | 2010-12-27 | 2014-12-16 | Hoffmann-La Roche Inc. | Biaryl amide derivatives |
| US8877766B2 (en) * | 2013-02-15 | 2014-11-04 | Peter F. Kador | Neuroprotective multifunctional antioxidants and their monofunctional analogs |
| WO2014127816A1 (en) | 2013-02-21 | 2014-08-28 | Boehringer Ingelheim International Gmbh | Dihydropteridinones ii |
| EP3082422A4 (en) * | 2013-12-20 | 2017-07-05 | Biomed Valley Discoveries, Inc. | Cancer treatments using combinations of mek type i and erk inhibitors |
| RU2690188C2 (ru) * | 2017-05-26 | 2019-05-31 | Общество С Ограниченной Ответственностью "Фарминтерпрайсез" | Новый мультитаргетный препарат для лечения заболеваний у млекопитающих |
| IL296025A (en) * | 2020-03-02 | 2022-10-01 | Sironax Ltd | Proptosis inhibitors - diarylamine para-acetamides |
| WO2021198534A1 (en) | 2020-04-04 | 2021-10-07 | Oxurion NV | Plasma kallikrein inhibitors for use in the treatment of coronaviral disease |
| GB202018412D0 (en) * | 2020-11-23 | 2021-01-06 | Exscientia Ltd | Malt-1 modulators ii |
| WO2023148016A1 (en) | 2022-02-04 | 2023-08-10 | Oxurion NV | Biomarker for plasma kallikrein inhibitor therapy response |
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| WO2003004492A1 (en) * | 2001-07-03 | 2003-01-16 | Vertex Pharmaceuticals Incorporated | Isoxazolyl-pyrimidines as inhibitors of src and lck protein kinases |
| US6919343B2 (en) * | 2002-02-08 | 2005-07-19 | Merck & Co., Inc. | N-biphenyl(substituted methyl) aminocycloalkane-carboxamide derivatives |
| AU2003217728B2 (en) | 2002-02-08 | 2008-11-20 | Merck Sharp & Dohme Corp. | N-Biphenylmethyl aminocycloalkanecarboxamide derivatives |
| WO2004019868A2 (en) * | 2002-08-29 | 2004-03-11 | Merck & Co., Inc. | N-biarylmethyl aminocycloalkanecarboxamide derivatives |
| AU2004265300A1 (en) * | 2003-08-07 | 2005-02-24 | Merck & Co., Inc. | Sulfonyl substituted N-(biarylmethyl) aminocyclopropanecarboxamides |
| ATE423114T1 (de) * | 2004-03-02 | 2009-03-15 | Merck & Co Inc | Aminocyclopropancarbonsäureamidderivate als bradykininantagonisten |
| WO2006120176A2 (en) | 2005-05-11 | 2006-11-16 | Nycomed Gmbh | Combination of the pde4 inhibitor roflumilast and a tetrahydrobiopterin derivative |
| HUP0600808A3 (en) * | 2006-10-27 | 2008-09-29 | Richter Gedeon Nyrt | New benzamide derivatives as bradykinin antagonists, process for their preparation and pharmaceutical compositions containing them |
| HUP0600809A3 (en) * | 2006-10-27 | 2008-09-29 | Richter Gedeon Nyrt | New phenylsulfamoyl-benzamide derivatives as bradykinin antagonists, process and intermediates for their preparation and pharmaceutical compositions containing them |
| JP5238812B2 (ja) * | 2007-08-29 | 2013-07-17 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 新規ブラジキニンb1アンタゴニスト |
| MY153941A (en) * | 2009-02-26 | 2015-04-15 | Boehringer Ingelheim Int | Compounds as bradykinin b1 antagonists |
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